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PubMed2005

The use of Achilles tendon sonography to distinguish familial hypercholesterolemia from other genetic dyslipidemias.

OBJECTIVE: Achilles tendon (AT) xanthomas, specific for familial hypercholesterolemia (FH), may be clinically undetectable. We assessed the usefulness of AT sonography in the diagnosis of FH. METHODS AND RESULTS: Sonographic AT characteristics were evaluated in 127 subjects with FH (81 genetically ascertained), 84 familial combined hyperlipidemia, 79 polygenic hypercholesterolemia, and 88 normolipidemic controls. Abnormal echostructure (sonographic xanthoma) was noted only in FH. AT thickness was higher (P<0.001) in FH men and women compared with all of the other groups and, in FH mutation carriers but not in others, correlated positively with low-density lipoprotein cholesterol (r=0.345; P<0.001) and negatively with high-density lipoprotein cholesterol (r=-0.265, P=0.015). Thickness thresholds for the diagnosis of FH with specificity >80%, as were derived from receiver operating curves, were 5.3 and 5.7 mm in men < and >45 years, and 4.8 and 4.9 mm in women < and >50 years, respectively. In FH mutation carriers, sonographic findings increased the clinical diagnosis of xanthomas from 35 (43%) to 55 (68%). Using thresholds in validation sets of 70 genetically identified FH and 54 dyslipidemic non-FH correctly classified 80% and 88%, respectively. CONCLUSIONS: Sonographic AT characteristics are normal in non-FH dyslipidemias. Identification of suspected FH by ultrasound using sex- and age-specific AT thickness thresholds is recommended.

Achilles Tendon↗
PubMedDate not supplied

Low density lipoprotein kinetics in a family having defective low density lipoprotein receptors in which hypercholesterolemia is suppressed.

Heterozygous familial hypercholesterolemia (FH) usually presents with severe elevations of low density lipoprotein (LDL) cholesterol. Recently, a family with FH was described in which several members heterozygous for a mutation in the LDL receptor gene had normal LDL cholesterol levels. Kinetic studies of LDL apolipoprotein B (apo B) were conducted to determine the metabolic differences between the normolipidemic and hypercholesterolemic FH heterozygotes in the family. Studies were performed in 14 family members including the proband (who has homozygous FH), four FH heterozygotes with high LDL levels, four FH subjects with normolipidemia, and five healthy relatives without FH. The proband had a very low fractional catabolic rate (FCR) for LDL (0.15 pool/day). All the FH and non-FH subjects studied, excluding the FH homozygote, had higher than expected FCRs for LDL. The average FCRs for LDL of hypercholesterolemic and normocholesterolemic subjects were not significantly different (0.39 +/- 0.06 versus 0.37 +/- 0.02 pool/day), and these values were 70-80% of those in unaffected relatives. Compared with hypercholesterolemic FH heterozygotes, normolipidemic heterozygotes had much lower input rates for LDL (17.1 +/- author query macros2.6 versus 8.7 +/- 0.9 pools/day, respectively). These low input rates, together with the higher than usual FCRs for LDL, are responsible for the normal concentrations of LDL cholesterol in some of the FH heterozygotes. The low input of LDL could be due to either a decreased secretion of apo B-containing lipoproteins or an enhanced clearance of LDL precursor lipoproteins.

Adolescent↗
PubMed1992

Diagnosis of heterozygous familial hypercholesterolemia. DNA analysis complements clinical examination and analysis of serum lipid levels.

The concordance of clinical and molecular genetic diagnoses of heterozygous familial hypercholesterolemia (FH) was studied in 65 subjects (10 propositi and 55 first-degree relatives) from 10 families with FH. Nine propositi were carriers of the FH-Helsinki deletion of the low density lipoprotein (LDL) receptor gene, prevalent in the Finnish population, while a new deletion, extending from intron 14 to intron 15 of the LDL receptor gene, was identified in one family. Serum LDL cholesterol levels used in the clinical diagnosis (less than 5.0 mmol/l, not FH; 5.0-5.9 mmol/l, possible FH; greater than or equal to 6.0 mmol/l, FH; limits are 1 mmol/l lower for those less than 18 years) were derived from an authoritative recommendation. Tendon xanthomas constituted an additional criterion. With the DNA analysis as the reference, 55 (85%) subjects could be correctly classified clinically as FH patients or subjects without FH. The remaining 10 subjects were misclassified or were in the "possible FH" category. When the age- and sex-specific 95th percentile LDL cholesterol levels were used instead of the rigid values for both adults and children, the percentage of correct diagnoses rose to 95%. Common genetic polymorphisms of apolipoproteins E and B did not markedly affect LDL cholesterol levels in FH patients, whereas increasing age and obesity were associated with elevated LDL levels. In conclusion, DNA analysis is a valuable adjunct to the diagnosis of FH that is applicable to families with a known mutation of the LDL receptor gene. If DNA methods are not available, age- and sex-specific LDL levels should be used as an aid in the clinical diagnosis of FH.

Adolescent↗
PubMed1995

Differences in the phenotypic characteristics of subjects with familial defective apolipoprotein B-100 and familial hypercholesterolemia.

Familial defective apolipoprotein B-100 (FDB) is a recently identified autosomal-dominantly inherited disorder caused by a point mutation in the apolipoprotein (apo) B gene. To determine whether the phenotypic characteristics in FDB subjects are similar to those in subjects with familial hypercholesterolemia (FH), 76 kindreds fulfilling the clinical criteria for heterozygous FH/FDB were characterized using molecular biological techniques. Allele-specific polymerase chain reaction (PCR) at the apoB locus was used for diagnosis or exclusion of FDB. PCR-based methods for detection of two point mutations (V408M and P664L) at the LDL receptor (LDLR) locus, cosegregation analysis using eight restriction fragment length polymorphisms (RFLPs) at the LDLR locus, or the exclusion of FDB confirmed the clinical diagnosis of FH. Three kindreds were not included because of a missing cosegregation between a particular haplotype and the FH phenotype. We predicted that a similar number of kindreds would be detected in the two groups, assuming comparable prevalences of the diseases in our population and similar phenotypic characteristics. However, only nine kindreds were identified with the FDB mutation compared with 64 kindreds with FH (P < .0001). From these 73 kindreds, 28 FDB heterozygotes and 129 FH heterozygotes were compared using multivariate analysis. There were no differences between these two groups with respect to age, sex, and apoE genotype distribution, lipoprotein(a) concentrations, body mass index, blood pressure, and smoking habits. However, FDB subjects demonstrated significantly lower concentrations of total cholesterol (8.1 versus 10.2 mmol/L, P < .001), LDL cholesterol (6.3 versus 8.2 mmol/L, P < .001), and triglycerides (1.3 versus 1.8 mmol/L, P = .025) and higher concentrations of HDL cholesterol (1.4 versus 1.2 mmol/L, P = .015) than subjects with FH. In contrast to FH, female FDB subjects tended to have higher concentrations of total cholesterol (8.9 versus 7.5 mmol/L, P = .032) and LDL cholesterol (7.1 versus 5.7 mmol/L, P = .026) than FDB males. The same results regarding total and LDL cholesterol and sex differences were observed when individual data of 238 FDB and 415 FH subjects from the literature were compared. In addition, FDB subjects showed much larger total cholesterol fluctuations than FH subjects (median of intraindividual coefficients of variation: FDB, 14.5%; FH, 5.3%; P < .001). In summary, these results demonstrate that FDB subjects tend to have a milder form of hyperlipoproteinemia than FH subjects and that only a part of the subjects with FDB fulfill the established criteria for identifying FH.

Adolescent↗
PubMed1980

Structure, immunology, and cell reactivity of low density lipoprotein from umbilical vein of a newborn type II homozygote.

In this report we compare the cord blood lipoproteins of a newborn boy homozygote who has low density lipoprotein (LDL) receptor-defective familial hypercholesterolemia (FH) with the lipoproteins from cord blood of normal newborns. Plasma LDL-cholesterol and apoprotein (Apo)B were 612 and 233 mg/dl (vs. 31+/-16 and 24+/-12 mg/dl, respectively, for normals, n = 21). LDL-cholesterol/ApoB ratio was 2.6 vs. 1.4+/-0.5. Levels of ApoA-I, ApoA-II, and HDL-cholesterol were similar to normal cord plasma. Thus, the lipoprotein abnormality is apparent at birth and is definitely present in LDL. Abnormalities in other lipoprotein, lipid, and in plasma apoprotein levels were not detected. On zonal ultracentrifugation, FH LDL was comprised of two populations (LDL(a) and LDL(b)), both faster floating than normal cord LDL (LDL(c)). This difference was due to the larger diameters of the particles on electron microscopy (LDL(a) = 276A+/-32 and LDL(b) = 260A+/-38 vs. LDL(c) = 237A+/-26, n = 200 each, mean+/-1 SD), and their higher contents of lipids relative to protein (86 and 82% vs. 74%, LDL(a), LDL(b), and LDL(c), respectively). More than 94% of the protein in both the FH and the normal preparations consisted of ApoB. FH LDL were more effective than control LDL in competing with (125)I-LDL (adult) for limiting amounts of anti-LDL antibodies in radioimmunoassay. FH LDL also competed more effectively for binding to LDL receptors on cultured fibroblasts at 4 degrees C, and FH LDL also delivered more cholesterol into the cells. Cells grown in lipoprotein-deficient serum contained 44+/-2 mug cholesterol/mg cell protein, incubation of cells for 18 h at 37 degrees C in 5 mug/ml FH LDL (protein) or in normal LDL raised cellular cholesterol levels to 75+/-2 and 60+/-2 mug/mg, respectively.LDL isolated from the FH patient's plasma at 6 mo of age and from his brother's plasma (a 5-yr-old boy FH homozygote) were similar to LDL isolated from normolipemic subjects in flotation properties, chemical composition, and immunochemical and cell reactivity. The fact that differences between normal cord LDL and FH cord LDL were present at birth, but that the differences between control and FH LDL were no longer present postnatally suggests that the altered immunologic and cell interactive properties of FH cord LDL were probably related to its unusually high contents of core lipids.

Child↗
PubMed1998

Familial hyperaldosteronism type II: description of a large kindred and exclusion of the aldosterone synthase (CYP11B2) gene.

Familial hyperaldosteronism type II (FH-II) is characterized by autosomal dominant inheritance and hypersecretion of aldosterone due to adrenocortical hyperplasia or an aldosterone-producing adenoma; unlike FH type I (FH-I), hyperaldosteronism in FH-II is not suppressible by dexamethasone. Of a total of 17 FH-II families with 44 affected members, we studied a large kindred with 7 affected members that was informative for linkage analysis. Family members were screened with the aldosterone/PRA ratio test; patients with aldosterone/PRA ratio greater than 25 underwent fludrocortisone/salt suppression testing for confirmation of autonomous aldosterone secretion. Postural testing, adrenal gland imaging, and adrenal venous sampling were also performed. Individuals affected by FH-II demonstrated lack of suppression of plasma A levels after 4 days of dexamethasone treatment (0.5 mg every 6 h). All patients had negative genetic testing for the defect associated with FH-I, the CYP11B1/CYP11B2 hybrid gene. Genetic linkage was then examined between FH-II and aldosterone synthase (the CYP11B2 gene) on chromosome 8q. A polyadenylase repeat within the 5'-region of the CYP11B2 gene and 9 other markers covering an approximately 80-centimorgan area on chromosome 8q21-8qtel were genotyped and analyzed for linkage. Two-point logarithm of odds scores were negative and ranged from -12.6 for the CYP11B2 polymorphic marker to -0.98 for the D8S527 marker at a recombination distance (theta) of 0. Multipoint logarithm of odds score analysis confirmed the exclusion of the chromosome 8q21-8qtel area as a region harboring the candidate gene for FH-II in this family. We conclude that FH-II shares autosomal dominant inheritance and hyperaldosteronism with FH-I, but, as demonstrated by the large kindred investigated in this report, it is clinically and genetically distinct. Linkage analysis demonstrated that the CYP11B2 gene is not responsible for FH-II in this family; furthermore, chromosome 8q21-8qtel most likely does not harbor the genetic defect in this kindred.

Aldosterone↗
PubMed2000

Treatment of central precocious puberty: lessons from a 15 years prospective trial. German Decapeptyl Study Group.

There is still controversy about the auxological outcome of GnRH agonist treatment in patients with CPP and about the favorable age and auxological characteristics at start of treatment for achieving a normal final height (FH) or for preserving height potential. We analyzed the FH data of 52 young women from a prospective multicentric trial which was started in 1985. The aim of this analysis was to determine factors that may predict a favorable FH or a good height gain. Chronological age (CA) was 5.2 +/- 2.1 yr (+/- SD) at start of puberty, 6.2 +/- 2.0 yr at start of triptorelin depot treatment, 11.1 +/- 1.1 yr at end of treatment, and 16.7 +/- 2.6 yr at FH evaluation. After 4.8 +/- 2.2 yr (1.1-9.9 yr) of treatment duration, FH was 160.6 +/- 8.0 cm (vs 154.9 +/- 9.6 cm of initial height prediction [PAH], p<0.05). A FH within TH range or in excess of mean TH was achieved by 78% or 41% of patients. FH was above the 3rd percentile of the normal German population in 29% of patients (63% had an initial PAH < 156 cm). The group of patients with start of puberty at age < or = 6 yr (Group 1) showed a significantly higher height gain (FH - initial PAH) and lower height deficit compared to TH than older patients (Group 2). Furthermore, the percentage of patients from Group 1 reaching TH range or mean TH showed a significant increase with GnRH agonist treatment whereas this was not the case in Group 2. Stepwise regression analysis showed that height SDS at end of treatment, age at menarche, bone age (BA) at start of treatment, and BA advancement at end of treatment were determinants of FH (r2=0.923). Initial BA advancement and treatment duration were the factors that explained 68% of the variability of height gain. Although BA advancement at initiation of treatment was negatively associated with FH it was a positive predictor of height gain. In addition, height gain correlated significantly with CA and BA at start of treatment (r= -0.430, p=0.004 and r=0.359, p=0.018). Growth after interruption of treatment had no significant predictive effect on FH. It is concluded that a higher percentage of patients below 6 yr of age at start of puberty do profit from GnRH agonist treatment with respect to achieving a normal FH. BA, BA advancement, and height SDS at treatment start are important factors for determining outcome.

Aging↗
PubMed1988

Acute alcohol intoxication in socially drinking female and male offspring of alcoholic fathers.

Alcohol pharmacokinetics, mood-state alterations and psychomotor performance were investigated in women and men at risk for developing alcoholism. Estimated body water was used to calculate the alcohol dose in an effort to eliminate differences in alcohol pharmacokinetics between women and men due to differences in body composition. Differences were not detected between women and men or family history groups (family history positive, FH +, and family history negative, FH-) on absorption time, peak blood alcohol level (BAL), elimination time, or area under the blood alcohol curve (AUC). FH + men reported no central stimulant effects at peak BAL on the Sensation Scale, whereas FH- men and women all reported central stimulant effects. Further, FH + men reported a decrease in anxiety after the ingestion of alcohol. Acute intoxication did not affect performance in the FH + group on a finger-tapping task. In the FH - group, the dominant hand was significantly impaired during the ascending limb of the blood alcohol curve and recovered during the descending limb. Differences between family history groups or sex were not detected on a grooved-pegboard task. Results indicated that FH + men may experience alcohol differently from the FH - group and FH + women. FH + women also showed different reactions to acute alcohol than the FH - group. However, these differences were not as consistent across tasks.

Adult↗
PubMed1995

Cognitive recovery with abstinence and its relationship to family history for alcoholism.

OBJECTIVE: The relationship between drinking relapse and family history for alcoholism to cognitive functioning was investigated in alcoholics who completed a 28-day inpatient treatment program. METHOD: The current study examined 144 primary alcoholics who completed a battery of cognitive tests on admission to treatment and at a 3-4 month follow-up visit. Participants were classified as either family history positive (FH+) (n = 86) or family history negative (FH-) (n = 58) based on information on alcohol dependence in first degree relatives. The subjects were further classified as drinkers (n = 56) or abstainers (n = 88) at follow-up, based upon information gathered about their drinking practices during the interval. RESULTS: There were no differences between the groups based on family history status at admission to treatment. Comparisons made at follow-up revealed that the abstainers' (both FH+ and FH-) performance improved. The FH+ drinkers' performance was worse than that of both the FH- drinkers and the FH+ abstainers at follow-up. The poor performance of the FH+ drinkers relative to the FH- drinkers was not attributable to differences in drinking consumption during the test-retest interval. CONCLUSIONS: These results suggest that alcoholics who maintain abstinence following treatment show improvement on cognitive testing at follow-up; both FH+ and FH- abstainers showed improvement, indicating that a positive family history of alcoholism does not impede recovery that occurs with abstinence. The most important finding, however, is that the FH+ drinkers show greater deterioration at follow-up compared to the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2006

Premenstrual symptomatology, alcohol consumption, and family history of alcoholism in women with premenstrual syndrome.

OBJECTIVE: The purpose of this study was to examine the relationship among family history of alcoholism (FH), premenstrual syndrome (PMS) symptoms, and alcohol consumption in women with a PMS diagnosis. METHOD: Participants (N = 46) were predominantly white (73%) women, of whom 17 (37%) reported multigenerational alcoholism on the paternal side (FH positive [FH+]) using the Family Alcohol and Drug Survey. Subjects recorded alcohol consumption and PMS symptoms using a daily record form for 3 consecutive months. RESULTS: Demographics and alcohol consumption during the follicular phase (FOL) and premenstrual phase (PREM) of the menstrual cycle did not differ by FH; however, change in drinking from FOL to PREM was greater in FH+ (mean change = 2.78 drinks/week) versus FH negative (FH-; mean change = -0.72 drinks/week) women. During PREM, FH- women reported more PMS symptomatology compared with FH+ women, and alcohol consumption during PREM was positively correlated with ratings of bloating, craving for alcohol, craving for food, and low energy in FH- but not FH+ women. CONCLUSIONS: Although FH+ women increased their drinking premenstrually, such use was unrelated to PMS symptom severity.

Adult↗
PubMed2006

The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance.

Neisseria meningitidis binds factor H (fH), a key regulator of the alternative complement pathway. A approximately 29 kD fH-binding protein expressed in the meningococcal outer membrane was identified by mass spectrometry as GNA1870, a lipoprotein currently under evaluation as a broad-spectrum meningococcal vaccine candidate. GNA1870 was confirmed as the fH ligand on intact bacteria by 1) abrogation of fH binding upon deleting GNA1870, and 2) blocking fH binding by anti-GNA1870 mAbs. fH bound to whole bacteria and purified rGNA1870 representing each of the three variant GNA1870 families. We showed that the amount of fH binding correlated with the level of bacterial GNA1870 expression. High levels of variant 1 GNA1870 expression (either by allelic replacement of gna1870 or by plasmid-driven high-level expression) in strains that otherwise were low-level GNA1870 expressers (and bound low amounts of fH by flow cytometry) restored high levels of fH binding. Diminished fH binding to the GNA1870 deletion mutants was accompanied by enhanced C3 binding and increased killing of the mutants. Conversely, high levels of GNA1870 expression and fH binding enhanced serum resistance. Our findings support the hypothesis that inhibiting the binding of a complement down-regulator protein to the neisserial surface by specific Ab may enhance intrinsic bactericidal activity of the Ab, resulting in two distinct mechanisms of Ab-mediated vaccine efficacy. These data provide further support for inclusion of this molecule in a meningococcal vaccine. To reflect the critical function of this molecule, we suggest calling it fH-binding protein.

Adjuvants, Immunologic↗
PubMed2000

Screening for hypercholesterolaemia versus case finding for familial hypercholesterolaemia: a systematic review and cost-effectiveness analysis.

BACKGROUND: In the majority of people with familial hypercholesterolaemia (FH) the disorder is caused by a mutation of the low-density lipoprotein receptor gene that impairs its proper function, resulting in very high levels of plasma cholesterol. Such levels result in early and severe atherosclerosis, and hence substantial excess mortality from coronary heart disease. Most people with FH are undiagnosed or only diagnosed after their first coronary event, but early detection and treatment with hydroxymethylglutaryl-coenzyme (HMG CoA) reductase inhibitors (statins) can reduce morbidity and mortality. The prevalence of FH in the UK population is estimated to be 1 in 500, which means that approximately 110,000 people are affected. OBJECTIVES: To evaluate whether screening for FH is appropriate. To determine which system of screening is most acceptable and cost-effective. To assess the deleterious psychosocial effects of genetic and clinical screening for an asymptomatic treatable inherited condition. To assess whether the risks of screening outweigh potential benefits. METHODS DATA SOURCES: Relevant papers were identified through a search of the electronic databases. Additional papers referenced in the search material were identified and collected. Known researchers in the field were contacted and asked to supply information on unpublished or ongoing studies. INCLUSION/EXCLUSION CRITERIA: SCREENING AND TREATMENT: The review included studies of the mortality and morbidity associated with FH, the effectiveness and cost of treatment (ignoring pre-statin therapies in adults), and of the effectiveness or cost of possible screening strategies for FH. PSYCHOSOCIAL EFFECTS OF SCREENING: The search for papers on the psychological and social effects of screening for a treatable inherited condition was limited to the last 5 years because recent developments in genetic testing have changed the nature and implications of such screening tests. Papers focusing on genetic testing for FH and breast cancer were included. Papers relating to the risk of coronary heart disease with similarly modifiable outcome (non-FH) were also included. DATA EXTRACTION AND ASSESSMENT OF VALIDITY: A data assessment tool was designed to assess the quality and validity of the papers which reported primary data for the social and psychological effects of screening. Available guidelines for systematically reviewing papers concentrated on quantitative methods, and were of limited relevance. An algorithm was developed which could be used for both the qualitative and quantitative literature. MODELLING METHODS: A model was constructed to investigate the relative cost and effectiveness of various forms of population screening (universal or opportunistic) and case-finding screening (screening relatives of known FH cases). All strategies involved a two-stage process: first, identifying those people with cholesterol levels sufficiently elevated to be compatible with a diagnosis of FH, and then either making the diagnosis based on clinical signs and a family history of coronary disease or carrying out genetic tests. Cost-effectiveness has been measured in terms of incremental cost per year of life gained. RESULTS: MODELLING COST-EFFECTIVENESS: FH is a life-threatening condition with a long presymptomatic state. Diagnostic tests are reasonably reliable and acceptable, and treatment with statins substantially improves prognosis. Therefore, it is appropriate to consider systematic screening for this condition. Case finding amongst relatives of FH cases was the most cost-effective strategy, and universal systematic screening the least cost-effective. However, when targeted at young people (16 year olds) universal screening was also cost-effective. Screening patients admitted to hospital with premature myocardial infarction was also relatively cost-effective. Screening is least cost-effective in men aged over 35 years, because the gains in life expectancy are small. (ABSTRACT TRUNCA

Adult↗
PubMed1995

Molecular characterization of minor gene rearrangements in Finnish patients with heterozygous familial hypercholesterolemia: identification of two common missense mutations (Gly823-->Asp and Leu380-->His) and eight rare mutations of the LDL receptor gene.

Two deletions of the low-density lipoprotein (LDL) receptor gene were previously shown to account for about two thirds of all mutations causing familial hypercholesterolemia (FH) in Finland. We screened the DNA samples from a cohort representing the remaining 30% of Finnish heterozygous FH patients by amplifying all the 18 exons of the receptor gene by PCR and searching for DNA variations with the SSCP technique. Ten novel mutations were identified, comprising two nonsense and seven missense mutations as well as one frameshift mutation caused by a 13-bp deletion. A single nucleotide change, substituting adenine for guanidine at position 2533 and resulting in an amino acid change of glycine to aspartic acid at codon 823, was found in DNA samples from 14 unrelated FH probands. This mutation (FH-Turku) affects the sequence encoding the putative basolateral sorting signal of the LDL receptor protein; however, the exact functional consequences of this mutation are yet to be examined. The FH-Turku gene and another point mutation (Leu380-->His or FH-Pori) together account for approximately 8% of the FH-causing genes in Finland and are particularly common among FH patients from the southwestern part of the country (combined, 30%). Primer-introduced restriction analysis was applied for convenient assay of the FH-Turku and FH-Pori point mutations. In conclusion, this paper demonstrates the unique genetic background of FH in Finland and describes a commonly occurring FH gene with a missense mutation closest to the C terminus thus far reported.

Base Sequence↗
PubMed1994

Two founder mutations in the LDL receptor gene in Norwegian familial hypercholesterolemia subjects.

DNA from 20 unrelated familial hypercholesterolemia (FH) subjects were studied by analysis of single-strand conformation polymorphisms (SSCP) for mutations in exon 3 of the low density lipoprotein (LDL) receptor gene. Four different SSCP patterns were observed. The underlying mutations were characterized by DNA sequencing. One pattern represented the wild-type sequence. Another pattern represented a C-->G mutation (FH-Svartor) that changes codon 78 into the amber stop codon. The two other patterns represented heterozygosity and homozygosity, respectively, for a G-->A splice donor mutation (FH-Elverum) in intron 3. Based upon two PCR-based assays, the frequencies of FH-Svartor and FH-Elverum among 267 unrelated FH subjects, were 8% and 25%, respectively. FH Svartor was located on a chromosome with haplotype 3 in all five families where haplotype analysis were performed. FH Elverum was located on haplotype 2 in 16 out of 20 families. The two mutations must be considered founder mutations in the Norwegian population, and their existence will be clinically useful in diagnosing FH. The presence of two founder mutations together with previously published data on the prevalence of FH in Norway, indicate that FH may be a more common disease in Norway than previously thought.

Base Sequence↗
PubMed2004

No genetic linkage or molecular evidence for involvement of the PCSK9, ARH or CYP7A1 genes in the Familial Hypercholesterolemia phenotype in a sample of Danish families without pathogenic mutations in the LDL receptor and apoB genes.

A locus on chromosome 1p34.1-p32 has been linked to autosomal dominant Familial Hypercholesterolemia (FH) and is termed the third FH locus. We tested whether this third FH locus is linked to the FH phenotype in 20 Danish families, with 158 members, without pathogenic mutations in the genes, encoding the low-density lipoprotein (LDL) receptor or apolipoprotein B (apoB). We could exclude the third FH locus as a cause of FH by genetic linkage analysis in the families taken together. Since haplotype analysis of each family nevertheless suggested that the FH phenotype co-segregated in a manner consistent with linkage to the third FH locus in three small pedigrees, we performed sequencing analysis without being able to demonstrate mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, the main candidate gene in the third FH locus. By the same combination of genetic linkage and molecular analysis we could also exclude mutations in the gene for the LDL receptor adaptor protein and in the gene for cholesterol-7-alpha-hydroxylase as causes of FH in our sample. Although not indicating linkage to any known loci, our data still indicate that another dominant gene may be involved in causing a FH phenotype.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Elevated serum levels of proinflammatory cytokines and biomarkers of matrix remodeling in never-treated patients with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a common inherited disorder of lipoprotein metabolism, whose origin involves mutations in the gene coding for the low-density lipoprotein receptor protein. Although FH is monogenic, wide variation occurs in the onset and severity of atherosclerosis in these patients. METHODS: Since data on levels of inflammatory proteins and/or active factors in FH patients who have never received lipid-lowering treatment are lacking, serum levels of MMP-3, active MMP-9 and TIMP-1 as well as pro-inflammatory cytokines (TNF-alpha, IL-18) were determined in never-treated homozygous FH Moroccan patients (n=4) and compared to those of heterozygous FH subjects (n=7) and of healthy control subjects (n=5). RESULTS: When compared to controls, homozygous FH patients exhibited levels of active MMP-9 and TIMP-1 (p<0.05), and of both high sensitive-CRP and IL-18 which were significantly elevated (p<0.05 and p<0.01, respectively). In heterozygous FH patients, intermediate values between FH homozygotes and healthy controls were observed for these markers, with the exception of MMP-9 activity whose levels were significantly elevated (p<0.05). Multivariate analysis revealed a positive correlation between apolipoprotein B, TIMP-1 and IL-18 levels, and between hs-CRP and IL-18 (p<0.01). CONCLUSIONS: Although the sample size of this FH group was limited, our data suggest that nontreated homozygous FH patients, and to a lesser degree heterozygous FH patients, exhibit not only a markedly proinflammatory vascular state but also pronounced extracellular matrix remodeling, as reflected by elevated circulating levels of inflammatory cytokines and MMPs.

Adolescent↗
PubMed2005

Genetic influence on the clinical characteristics and outcome of febrile seizures--a retrospective study.

PURPOSE: To assess the influence of the family history (FH) of epilepsy or febrile seizures (FSs) on the clinical presentation of FSs and on their outcome. METHODS: We reviewed the charts of 482 children admitted to the Ste-Justine Hospital with FSs between 3 months and 6 years of age and followed for at least 5 years. RESULTS: Children with a positive FH of epilepsy (n=67) showed significantly more focal and recurrent FSs than those without such a FH. The risk of developing partial epilepsy (n=17) or generalized epilepsy (n=19) was significantly greater in children with focal or recurrent FSs, respectively. In children with focal FSs, only two out of 30 (6.7%) children with a negative FH of epilepsy developed partial epilepsy compared with four out of nine (44.4%) children with a positive FH. In children with recurrent FSs, as much as seven out of 34 (20.6%) children with a positive FH of epilepsy developed generalized epilepsy compared to only eight out of 161 (0.05%) of those with a negative FH. Nevertheless, when not taking into account the clinical presentation of FSs, the positive FH of epilepsy constituted a risk factor for developing generalized but not partial epilepsy. Finally, children with a positive FH of FSs (n=120) exhibited significantly more recurrent FSs than those without such a FH, but this did not modify the risk of epilepsy. CONCLUSION: The FH of FSs and/or epilepsy should be taken into account when evaluating the risk of FSs recurrence and of epilepsy.

Child↗
PubMed1999

Assessment by transesophageal echography of atherosclerosis of the descending thoracic aorta in patients with hypercholesterolemia.

This study assesses atheromatous lesions and aortic stiffness of the descending thoracic aorta (DTA) in patients with hyperlipidemia by transesophageal echography (TEE) and investigates the relations between atherosclerotic lesions and aging or serum cholesterol levels in these patients. Subjects included 16 patients with familial hypercholesterolemia (FH), 15 non-FH hyperlipidemic patients (non-FH), and 17 age-matched normal subjects. With use of TEE, the DTA was divided into 4 longitudinal portions of equal length, and the atheromatous lesions of each portion of DTA were scored according to their character and extension by biplane 2-dimensional TEE. The scores of atheromatous lesions from all 4 portions were added together to give the total atheromatous score. Then, after measuring the instantaneous dimensional changes of DTA in a cardiac cycle by M-mode TEE and blood pressure (BP) by a cuff method, we calculated the aortic stiffness parameter beta = ln(systolic BP/diastolic BP)/([Dmaximum - Dminimum]/Dminimum). The beta was significantly higher in FH and non-FH subjects than in normal subjects. In both FH and non-FH subjects, the total atheromatous score correlated with total serum cholesterol levels (r = 0.64 [p <0.01]; r = 0.58 [p <0.05], respectively). There were significant correlations between age and beta in all 3 groups (FH, r = 0.67 [p <0.005]; non-FH, r = 0.53 [p <0.05]; normal subjects, r = 0.49 [p <0.05]), and the slopes of the regression lines of FH and non-FH subjects were much steeper than those of normal subjects. The incidence of atherosis in the DTA was significantly higher in hyperlipidemic patients than in normal subjects, even among the younger members of the hyperlipidemic population with progressive aortic stiffness.

Age Factors↗